Synthesis of new tridentate chiral aminoalcohols by a multicomponent reaction and their evaluation as ligands for catalytic asymmetric Strecker reaction

Article abstract of DOI:10.1016/j.tet.2007.06.047

A one-step, multicomponent Mannich-type reaction between phenols, paraformaldehyde, and β-aminoalcohols in the presence of LiCl afforded N-2-hydroxybenzyloxazolidines with high ortho-selectivity. Hydrolytic or reductive ring opening of the oxazolidines pr

Full text of DOI:10.1016/j.tet.2007.06.047

Tetrahedron 63 (2007) 8727–8734
Synthesis of new tridentate chiral aminoalcohols by
a multicomponent reaction and their evaluation as ligands for
catalytic asymmetric Strecker reaction
!
Vorawit Banphavichit, Worawan Bhanthumnavin and Tirayut Vilaivan
*
Organic Synthesis Research Unit, Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
Received 22 March 2007; revised 30 May 2007; accepted 14 June 2007
Available online 21 June 2007
This paper is dedicated to late Dr. Vorawit Banphavichit
Abstract—A one-step, multicomponent Mannich-type reaction between phenols, paraformaldehyde, and b-aminoalcohols in the presence of
LiCl afforded N-2-hydroxybenzyloxazolidines with high ortho-selectivity. Hydrolytic or reductive ring opening of the oxazolidines provided
a series of N-salicyl-b-aminoalcohols in 84–92% overall yield. The synthesized compounds were evaluated as ligands for a titanium-catalyzed
catalytic asymmetric Strecker reaction. The reaction employing 10 mol % of catalyst provided the Strecker products in excellent yields and up
to 98% ee.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
the Schiff base 2 derived from b-aminoalcohols or their ester
precursors using an appropriate hydride transfer reagent.5,8
However, this method delivered only moderate yields and,
in our hands, the reduction failed with sterically hindered
substrates. Furthermore, the limited commercial availability
of substituted salicylaldehydes rendered this method of lim-
ited use. This prompted us to investigate a new methodology
to synthesize this useful class of ligand.
R2
R2
R3
OH
R3
OH
N
H
N
R1
R1
OH
OH
1
2
We considered a Mannich-type reaction between a phenol,
formaldehyde, and an aminoalcohol as a potential new route
to eliminate major problems associated with the synthesis of
1: namely, the limited variety of salicylaldehydes and low
yields.9 Although several hydroxyphenylbenzylamine deriv-
atives have been made by this type of condensation,9,10 very
few examples employed aminoalcohols as the amine compo-
nent.11,12 Most importantly, no synthesis of chiral tridentate
ligands of type 1 by this approach has been reported. It is
therefore our objective to develop a synthetic route for
ligand 1 employing this methodology, and to make a prelimi-
nary evaluation of their effectiveness as ligands for titanium-
catalyzed asymmetric Strecker reactions.
1,2-Aminoalcohols are versatile chiral auxiliaries and
ligands for catalytic asymmetric reactions.1 A number of
bidentate aminoalcohol ligands have been synthesized and
utilized in many asymmetric reactions, especially in con-
junction with dialkylzinc in asymmetric addition to carbonyl
compounds and imines.2 Relatively little work on tri- or
multidentate aminoalcohols have been reported.3 One of
the most notable examples is the prolinol-based multidentate
ligand.4 We have recently shown that the N-salicyl b-
aminoalcohol 1 is an effective ligand for titanium-catalyzed
asymmetric Strecker reactions.5 Similar ligands were shown
to be effective for cyanosilylation of aldehydes6 as well as
Michael additions of malonate esters to cyclic enones.7 A
classical way of making this class of ligand is to reduce
2. Results and discussion
The conditions for the three-component Mannich-type reac-
tion were optimized by reacting 40-hydroxybiphenyl and
phenol as representative phenols, (S)-valinol as a representa-
tive b-aminoalcohol, and excess of paraformaldehyde
(10 equiv). The reaction proceeded poorly in both protic
Keywords: Enantioselective; Chiral ligand; Catalyst; Strecker reaction;
Mannich reaction; Imine.
* Corresponding author. Tel.: +662 2187627; fax: +662 2187598; e-mail:
vtirayut@chula.ac.th
Deceased on 1st September 2006.
!
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.06.047

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V. Banphavichit et al. / Tetrahedron 63 (2007) 8727–8734
Table 1. Conditions for optimization of the three-component Mannich-type
reaction
Next, we investigated the conditions for hydrolytic ring
opening of the oxazolidines 3 to give the desired ligand 1.
Acid hydrolysis of oxazolidine or formacetal, e.g., aqueous
HCl, was not efficient due to the reversible nature of the re-
action. We have found that treatment of 3 with excess
(10 equiv) of hydroxylamine hydrochloride in methanol,
conditions previously applied for the cleavage of imines,13
cleanly afforded the expected products 1. The hydroxyl-
amine probably works by trapping the liberated formalde-
hyde, therefore prevented the reverse reaction.
OH
OH
paraformaldehyde, 80 °C
N
O
+
H2N
1.0 equiv Lewis acid, solvent
OH
R
R
3
Entry
R
Lewis acid
Solvent
Yield (%)
1
2
3
4
5
6
7
8
C6H5
—
—
EtOH
CH3CN
EtOH
CH3CN
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
CH3CN
EtOH
CH3CN
46
31
86
45
72
81
83
58
47
38
42
28
86
48
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
H
The two-step sequence, namely Mannich-type multicompo-
nent reaction followed by oxazolidine ring opening, was
applied to synthesize a number of chiral ligands 1 (Table
2). In most cases, the oxazolidine intermediates 3 were not
isolated but the crude products from the Mannich reaction
were directly hydrolyzed as described above to give 1 as
the final products. In cases where comparisons are available,
ligands 1 were obtained in consistently higher yields than
those from the sodium borohydride reduction method (en-
tries 1, 13–19, 23, and 24). Most of the phenols participated
LiCl
LiCl
LiBr
LiOTf
LiClO4
MgCl2
ZnCl2
CuCl2
—
9
10
11
12
13
14
H
H
H
—
LiCl
LiCl
Table 2. Synthesis of chiral aminoalcohols 1 from phenol and b-amino-
alcohols by multicomponent Mannich-type reaction to form oxazolidines
3 followed by hydrolytic ring opening
(EtOH) and aprotic (MeCN) solvents. Addition of stoichio-
metric amounts of a Lewis acid resulted in significant im-
provement of the yield (Table 1). It was finally found that
a combination of a lithium salt, preferably LiCl, as Lewis
acid and ethanol as solvent was optimal. The reactions
gave, instead of the expected ligand 1, isolable intermedi-
ates, which have been identified as oxazolidines 3a (from
40-hydroxybiphenyl) and 3b (from phenol). The structures
of oxazolidines 3 were distinguished from the alternative
benzoxazine structure 4 by NMR spectroscopy.12 The latter
was reported to be the product from condensation involving
phenols and simple amines in the presence of 2 equiv of
formaldehyde.9a Correlations between the aminal protons
(dH¼4.24 and 4.42 ppm in 3a; 4.21 and 4.37 ppm in 3b)
and 13C NMR signals of the aminoalcohol moiety
(dC¼68.3 and 70.7 ppm in 3a; 68.2 and 70.6 ppm in 3b for
the a- and b-carbons, respectively), and the absence of cor-
relations between these protons and aromatic carbons in
HMBC experiments strongly supported the oxazolidine
structures (Scheme 1). A very high ortho-selectivity with
respect to the position of alkylation on the phenolic ring
was observed with unsubstituted phenol. The high ortho-
selectivity could be explained by the chelating effect of the
lithium ion, making the alkylation at the ortho-position
highly favored (Scheme 1). Substitution of phenol with
anisole did not result in any product formation, indicating
the critical role of the free phenolic OH in mediating the
reaction.
OH
OH
R2
R3
OH
paraformaldehyde, 80 °C
LiCl 1equiv, EtOH
N
O
+
H2N
R2
R1
R1
R3
3
R2
R3
NH2OH.HCl
MeOH
N
H
OH
R1
OH
1
Entry
Ligand
R1
R2
R3
Yielda (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
1s
4-C6H5
H
iPr
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
85
iPr
87 (75)
86
86
88
87
84
88
84
92
2-C6H5
4-Me
2-Me
4-tBu
2-tBu
4-Cl
2-Cl
4-OMe
2,4-diMe
2,4-ditBu
H
H
H
H
H
H
H
iPr
iPr
iPr
iPr
iPr
iPr
9
iPr
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
iPr
iPr
83
87
iPr
Ph
86 (73)
85 (50)
84 (72)
86 (74)
62 (51)
60 (49)
88 (74)
86
85
88
85 (74)
85 (0)
84
iBu
cHexCH2
sBu
Me
H
H
O
PhCH2
PhCH2
PhCH2
PhCH2
tBu
1t
3-C6H5
3-Cl
3-Me
H
H
H
OH
R
Li
H
1u
1v
1w
1x
1y
1z
H
H
N
R2
O
O
N
N
O
OH
2,4-ditBu
4-Me
2-Me
tBu
tBu
R1
tBu
89
R
4a R = Ph
4b R = H
3a R = Ph
3b R = H
a
Yields of pure ligands obtained from two-step reactions. Values in paren-
theses are the yields obtained by NaBH4 reduction of Schiff bases 2
formed in situ between appropriate salicylaldehydes and aminoalcohols.
Scheme 1.

V. Banphavichit et al. / Tetrahedron 63 (2007) 8727–8734
8729
Table 4. Evaluation of the ligands for asymmetric Strecker reaction
in the reaction well, except strongly deactivated phenols
such as 4-nitrophenol. Both a- and b-naphthols gave only
tarry materials. 2,20-Dihydroxybiphenyl and binaphthol
were inert under these conditions probably due to the chelat-
ing ability of these phenols, which inactivated the Lewis acid
catalyst. It should be emphasized again that the Mannich
reaction is very highly ortho-selective. para-Substituted
products could neither be isolated nor observed in the crude
reaction mixture. Even for 3-substituted phenol, only the less
hindered ortho-position reacted (entries 20–22). Since a vari-
ety of phenols are commercially available, a great diversity
of the salicyl moiety can easily be made. Furthermore, the
reaction is also applicable for preparing highly sterically
hindered ligands such as 1m (entry 24), which could not
be prepared by conventional methods due to the inertness
of its Schiff base precursor toward a number of reducing
agents.
1 or 5 (10 mol%)
Ti(OiPr)4 (10 mol%)
HN
N
TMSCN 2 equiv, toluene, -5-0 °C
CN
H
S
6
7
Entry
Ligand
Conversiona (%)
eeb (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
1s
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
82
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
78
98 (97)
97
41
97
79
93
5
93
43
94
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
It is known that oxazolidines may undergo a reductive ring
opening with NaBH4 in the presence of a Brønsted or a Lewis
acid to give exclusively N-methylated aminoalcohols as a
result of stereoelectronic effects.14 The oxazolidines 3
when treated with NaBH4/TFA should therefore provide
the N-methylated ligands 5. Some representative N-methyl-
ated ligands have been successfully synthesized in this way
(Table 3). Although the yields of the ligands 5 were gener-
ally not as good as the corresponding NH ligands 1, the
method provided a very concise access to N-methylated
ligands 5, which are also potentially useful ligands for cata-
lytic asymmetric reactions.
47
11
89 (89)
85 (84)
85 (85)
98 (98)
75 (73)
0 (0)
98 (98)
82
1t
1u
1v
1w
1x
1y
1z
5a
5b
5c
5d
5e
5f
78
90
98 (98)
14
97
>99
>99
>99
>99
>99
>99
>99
>99
83
0
24
0
11
14
8
Strecker reaction of N-benzhydrylimine 6 with TMSCN in
the presence of 1-Ti(OiPr)4 and 5-Ti(OiPr)4 complexes
were performed under the conditions reported by Banpha-
vichit et al. (Table 4).5a In cases where enantioselectivities
were observed, the (S)-enantiomer of the Strecker product 7
was preferentially formed. When comparisons are available,
practically identical enantioselectivities were obtained for
Determined by 1H NMR spectroscopy.
a
Determined by 1H NMR spectroscopy after addition of (S)-camphorsul-
fonic acid as chiral solvating agent.5a Values in parentheses are obtained
from ligands prepared using NaBH4 reduction method.5a
b
Table 3. Synthesis of N-methylated aminoalcohol 5 from phenols and b-
aminoalcohols by multicomponent Mannich-type reaction to form oxazol-
idine 3 followed by reductive ring opening with TFA/NaBH4
ligands prepared by Mannich reaction and NaBH4 reduc-
tion. The results confirmed previous observation that the
bulkiness of the b-substituent on the chiral N-salicyl-b-
aminoalcohol plays a significant role in determining the
degree of enantioselectivity. The presence of substituents
at ortho- or meta-positions on the salicyl moiety appeared
to decrease the enantioselectivity, most notably when the
substituent was sterically hindered. On the other hand,
the presence of para-substituent was well tolerated.
Although none of the new ligands provided better enantio-
selectivity than those already discovered,5 the results sug-
gest the possibilities of functionalization of the 4-position
of the salicyl moiety, for example, immobilization of the
ligand, without negative effects on the yield and enantio-
selectivity. It is noteworthy that even though all N-methyl-
ated ligands could catalyze the reaction, only very poor
enantioselectivities were observed (Table 4). The presence
of the free NH group in the ligand therefore appears to play
a significant role in controlling the enantioselectivity of the
reaction.
OH
OH
R2
R3
OH
paraformaldehyde, 80 °C
LiCl 1equiv, EtOH
N
O
+
H2N
R2
R1
R1
R3
3
R2
R3
NaBH4-TFA
THF
N
OH
R1
OH
5
Entry
Ligand
R1
tBu
R2
R3
Yielda (%)
b
1
2
3
4
5
6
5a
5b
5c
5d
5e
5f
–C6H4CH2–
61
62
60
60
57
58
H
CH2Ph
tBu
Ph
H
H
H
H
H
2,4-ditBu
4-Ph
3-Me
iPr
3-Ph
iPr
a
Yields of pure ligands obtained from two-step reactions.
(1R,2S) isomer.
b

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V. Banphavichit et al. / Tetrahedron 63 (2007) 8727–8734
3. Conclusions
The partially purified oxazolidine was dissolved in methanol
(5 mL) and treated with hydroxylamine hydrochloride
(5.0 mmol, 10 equiv). The reaction mixture was vigorously
stirred for 2 h or until the reaction went to completion (mon-
itored by TLC). After a usual aqueous work-up, the crude
product was purified by flash column chromatography using
hexanes and ethyl acetate as eluant to obtain the chiral
N-salicyl-b-aminoalcohols 1.
An efficient synthetic methodology for the preparation of
N-salicyl-b-aminoalcohol ligands has been developed. The
procedure was based on a multicomponent Mannich-type
reaction to form an oxazolidine intermediate. Hydrolytic
ring opening of the oxazolidines provided a series of chiral
N-salicyl-b-aminoalcohol ligands 1 in high yields. Alterna-
tive reductive ring opening afforded the corresponding
N-methylated ligands 5 in moderate yields. The 1:1 com-
plexes of Ti(OiPr)4 and 1 were highly effective catalysts
for enantioselective Strecker reactions of aldimines. Ligands
1 bearing a relatively sterically hindered substituent at the
b-position (R2) and without a substituent at the ortho-
position of the salicyl moiety gave the Strecker product in
excellent yields and enantioselectivities.
Ligands 1b, 1m–1s, and 1w have been previously synthe-
sized and characterization data reported.5
4.3. Spectroscopic data of selected oxazolidine deriva-
tives
4.3.1. N-(20-Hydroxy-30-biphenyl)methyl-(S)-4-isopropyl-
oxazolidine (3a). Colorless oil; [a]2D8 +0.84 (c 2.6, CHCl3);
1H NMR (CDCl3, 400 MHz): d 0.92 and 1.15 (6H, 2ꢁd,
J¼7.0 Hz, CH(CH3)2), 1.82 (1H, m, CH(CH3)2), 2.82 (1H,
m, NCHCH(CH3)2), 3.59 (1H, dd, J¼6.2, 8.6 Hz,
CHCHaHbO), 3.96 and 4.05 (1H, AB system, J¼14.0 Hz,
ArCH2N), 4.12 (1H, apparent t, J¼8.6 Hz, CHCHaHbO),
4.24 (1H, AB, J¼6.4 Hz, NCHaHbO), 4.42 (1H, AB, J¼
6.2 Hz, NCHaHbO), 6.97 (1H, d, J¼8.6 Hz, Ar), 7.25 (1H,
s, Ar), 7.32 (1H, m, Ar), 7.40–7.50 (3H, m, Ar), 7.56 (2H,
d, J¼7.8 Hz, Ar); 13C NMR (CDCl3, 100 MHz): 18.7,
20.1, 30.9, 59.4, 68.3, 70.7, 84.6, 116.8, 126.6, 127.5,
127.8, 128.7, 132.6, 140.8, 157.2; IR (film, nmax, cmꢂ1):
3020 (br), 2962 (w), 1606 (w), 1482 (w), 1266 (w); HRMS
(FAB+) calcd for C19H23NO2: 297.1729, found: 297.1733.
4. Experimental
4.1. General
Melting points were measured on an Electrothermal 9100
melting point apparatus. The optical rotations were mea-
sured at ambient temperature with a Jasco P-1010 polari-
meter. Proton (1H) and carbon (13C) nuclear magnetic
resonance (NMR) spectra were recorded on a Varian
Mercury-400 Plus operating at 400 (1H) and 100 MHz
(13C), respectively. Infrared spectra were recorded on a
Nicolet Impact 410 spectrometer, as a thin film on NaCl
plates. The characteristic absorption is reported as broad
(br), medium (m), or weak (w). High resolution mass spectra
were recorded on a JEOL JMS-700T (Osaka City University,
Japan) or Finnigan Mat High Resolution Mass Spectrometer
(Chulabhorn Research Institute, Bangkok) using the Fast
atom bombardment (FAB+) ionization method. Elemental
analysis results were analyzed on CHNS/O analyzer (Per-
kin–Elmer PE2400 Series II) at Scientific and Technological
Research Equipment Centre, Chulalongkorn University.
4.3.2. N-(20-Hydroxyphenyl)methyl-(S)-4-isopropylox-
azolidine (3b). Colorless oil; [a]2D8 ꢂ2.84 (c 2.8, CHCl3);
1H NMR (CDCl3, 400 MHz): d 0.96 and 1.08 (6H, 2ꢁd, J¼
7.0 Hz, CH(CH3)2), 1.79 (1H, m, CH(CH3)2), 2.80 (1H, m,
NCHCH(CH3)2), 3.56 (1H, dd, J¼7.0, 8.6 Hz, CHCHaHbO),
3.88 and 3.99 (1H, AB system, J¼13.2 Hz, ArCH2N), 4.15
(1H, apparent t, J¼7.8 Hz, CHCHaHbO), 4.21 (1H, AB,
J¼6.2 Hz, NCHaHbO), 4.37 (1H, AB, J¼6.2 Hz, NCHaHbO),
6.83 (1H, apparent t, J¼7.8 Hz, Ar), 6.90 (1H, d, J¼7.8 Hz,
Ar), 7.01 (1H, d, J¼7.8 Hz, Ar), 7.23 (1H, apparent t,
J¼7.0 Hz, Ar); 13C NMR (CDCl3, 100 MHz): d 18.8, 20.0,
30.9, 59.3, 68.2, 70.6, 84.6, 116.4, 119.4, 122.2, 128.8,
129.2, 157.6; IR (film, nmax, cmꢂ1): 3080 (br), 2962 (br),
1591 (w), 1486 (m), 1254 (m); HRMS (FAB+) calcd for
C13H19NO2: 221.1416, found: 221.1420.
Chemicals were purchased from standard suppliers and
were used as received without purification. Commercial
grade solvents for column chromatography were distilled
before use. THF was distilled from sodium benzophenone
ketyl radical prior to use. Toluene for the reactions was of
˚
AR grade and dried with activated 4 A molecular sieves.
Other solvents for the reactions were of AR grade and
used without further purification. Unless otherwise stated,
all reactions were performed in oven-dried glassware under
ambient conditions.
4.4. Physical properties and spectroscopic and analytical
spectra of new ligands
4.4.1. N-(20-Hydroxy-50-biphenyl)methyl-(S)-2-amino-3-
methylbutanol (1a). White crystalline solid (121 mg,
85%); mp 132–133 ꢀC; [a]D24 ꢂ19.4 (c 1.2, CHCl3); 1H NMR
(CDCl3, 400 MHz): d 1.03 and 1.05 (6H, 2ꢁd, J¼6.8 Hz,
2ꢁCH3), 2.05 (1H, m, CH(CH3)2), 2.65 (1H, m, CHNH),
3.73 (1H, ABX, JAB¼11.2, JBX¼6.4 Hz, CHaHbOH), 3.87
(1H, ABX, JAB¼11.2, JAX¼3.6 Hz, CHaHbOH), 4.15 (1H,
AB, J¼13.6 Hz, CHaHbNH), 4.18 (1H, AB, J¼13.6 Hz,
CHaHbNH), 7.01 (1H, d, J¼8.4 Hz, Ar), 7.32 (2H, m, Ar),
7.45 (3H, m, Ar), 7.55 (2H, m, Ar); 13C NMR (CDCl3,
100 MHz): d 18.7, 19.3, 28.6, 51.2, 61.1, 64.1, 116.0,
119.1, 123.5, 126.7, 127.5, 128.0, 129.1, 129.3, 138.5, 155.3;
IR (film, nmax, cmꢂ1): 3410 (br), 2959 (w), 1597 (w), 1461
4.2. General procedure for the synthesis of chiral
N-salicyl-b-aminoalcohol ligands 1
A mixture of a phenol (0.5 mmol), paraformaldehyde
(250 mg, 10 equiv), an appropriate aminoalcohol
(0.5 mmol), and LiCl (0.5 mmol) was dissolved with 3 mL
ethanol in a screw-capped test tube. The reaction mixture
was heated in a heating block at 80 ꢀC for 18 h. Ethanol
was removed in vacuo and the crude products were purified
by flash column chromatography using hexanes and ethyl
acetate as eluant. At this stage, it is usually difficult to com-
pletely remove the contaminated phenols.

V. Banphavichit et al. / Tetrahedron 63 (2007) 8727–8734
8731
(m), 1429 (m), 1235 (w), 1074 (w); Anal. Calcd for
C18H23NO2: C, 75.76; H, 8.12; N, 4.91; Found: C, 75.78;
H, 8.22; N, 4.75%.
125.2, 125.6, 141.9, 155.5; IR (film, nmax, cmꢂ1): 3305
(br), 2959 (w), 1605 (w), 1500 (m), 1390 (w), 1259 (w),
1125 (w), 1045 (w); Anal. Calcd for C16H27NO2: C, 72.41;
H, 10.25; N, 5.28; Found: C, 72.30; H, 10.23; N, 5.14%.
4.4.2. N-(20-Hydroxy-30-biphenyl)methyl-(S)-2-amino-3-
methylbutanol (1c). White crystalline solid (123 mg,
86%); mp 135–136 ꢀC; [a]D24 +19.6 (c 1.3, CHCl3); 1H NMR
(CDCl3, 400 MHz): d 1.03 and 1.05 (6H, 2ꢁd, J¼6.8 Hz,
2ꢁCH3), 2.05 (1H, m, CH(CH3)2), 2.65 (1H, m, CHNH),
3.73 (1H, ABX, JAB¼11.2, JBX¼6.4 Hz, CHaHbOH), 3.87
(1H, ABX, JAB¼11.2, JAX¼3.6 Hz, CHaHbOH), 4.16 (2H,
s, CH2NH), 6.90 (1H, t, J¼8.4 Hz, Ar), 7.01 (1H, d, J¼
8.4 Hz, Ar), 7.32 (2H, m, Ar), 7.45 (2H, m, Ar), 7.55 (2H,
m, Ar); 13C NMR (CDCl3, 100 MHz): d 18.8, 19.3, 28.6,
51.2, 61.1, 64.1, 119.1, 123.7, 126.8, 127.7, 128.1, 129.2,
129.4, 130.0, 138.6, 155.1; IR (film, nmax, cmꢂ1): 3303
(br), 2961 (w), 1602 (w), 1460 (m), 1272 (w), 1074 (w);
Anal. Calcd for C18H23NO2: C, 75.76; H, 8.12; N, 4.91;
Found: C, 75.74; H, 8.11; N, 5.15%.
4.4.6. N-(30-tert-Butyl-20-hydroxyphenyl)methyl-(S)-2-
amino-3-methylbutanol (1g). Colorless oil (111 mg,
84%); [a]2D4 +15.4 (c 1.0, CHCl3); 1H NMR (CDCl3,
400 MHz): d 1.01 and 1.05 (6H, 2ꢁd, J¼6.8 Hz, 2ꢁCH3),
1.48 (9H, s, 3ꢁCH3), 1.99 (1H, m, CH(CH3)2), 2.55
(1H, m, CHNH), 3.68 (1H, ABX, JAB¼11.2, JBX¼5.6 Hz,
CHaHbOH), 3.84 (1H, ABX, JAB¼11.2, JAX¼4.0 Hz,
CHaHbOH), 4.03 (1H, AB, J¼13.6 Hz, CHaHbNH), 4.08
(1H, AB, J¼13.6 Hz, CHaHbNH), 6.78 (1H, apparent t,
J¼7.6 Hz, Ar), 6.94 (1H, d, J¼7.2 Hz, Ar), 7.25 (1H, d,
J¼8.0 Hz, Ar); 13C NMR (CDCl3, 100 MHz): d 19.0, 19.3,
28.7, 29.6, 34.7, 51.2, 61.0, 63.8, 118.5, 123.4, 126.1, 126.7,
137.1, 157.0; IR (film, nmax, cmꢂ1): 3315 (br), 2958 (w),
1592 (w), 1439 (m), 1240 (w), 1083 (w); Anal. Calcd for
C16H27NO2: C, 72.41; H, 10.25; N, 5.28; Found: C, 72.24;
H, 10.34; N, 5.28%.
4.4.3. N-(20-Hydroxy-50-methylphenyl)methyl-(S)-2-
amino-3-methylbutanol (1d). White crystalline solid
(96 mg, 86%); mp 58–59 ꢀC; [a]D24 +18.0 (c 1.2, CHCl3);
1H NMR (CDCl3, 400 MHz): d 0.98 and 1.02 (6H, 2ꢁd, J¼
6.8 Hz, 2ꢁCH3), 1.95 (1H, m, CH(CH3)2), 2.27 (1H, s, CH3),
4.4.7. N-(50-Chloro-20-hydroxyphenyl)methyl-(S)-2-
amino-3-methylbutanol (1h). White crystalline solid
(107 mg, 88%); mp 98–100 ꢀC, [a]D24 +18.5 (c 1.3, CHCl3);
1H NMR (CDCl3, 400 MHz): d 0.98 and 1.02 (6H,
2ꢁd, J¼6.8 Hz, 2ꢁCH3), 1.95 (1H, m, CH(CH3)2), 2.53
(1H, m, CHNH), 3.65 (1H, ABX, JAB¼11.2, JBX¼6.4 Hz,
CHaHbOH), 3.83 (1H, ABX, JAB¼11.2, JAX¼3.6 Hz,
CHaHbOH), 4.00 (2H, s, CH2NH), 5.13 (br s, NH and OH),
6.78 (1H, d, J¼8.8 Hz, Ar), 6.99 (1H, s, Ar), 7.25 (1H, d,
J¼8.4 Hz, Ar); 13C NMR (CDCl3, 100 MHz): d 18.7, 19.3,
28.5, 50.2, 60.7, 64.0, 117.7, 123.6, 124.2, 128.2, 128.7,
156.8; IR (film, nmax, cmꢂ1): 3302 (br), 2962 (w), 1707
(w), 1589 (w), 1481 (m), 1262 (m), 1182 (w), 1088 (w);
Anal. Calcd for C12H18ClNO2: C, 59.13; H, 7.54; N, 5.75;
Found: C, 59.13; H, 7.62; N, 5.77%.
2.50 (1H, m, CHNH), 3.62 (1H, ABX, JAB¼11.2, JBX
¼
6.4 Hz, CHaHbOH), 3.81 (1H, ABX, JAB¼11.2, JAX¼3.6 Hz,
CHaHbOH), 3.97 (2H, s, CH2NH), 5.22 (br s, NH and OH),
6.76 (1H, d, J¼8.0 Hz, Ar), 6.82 (1H, s, Ar), 6.99 (1H, d,
J¼8.2 Hz, Ar); 13C NMR (CDCl3, 100 MHz): d 18.8, 19.2,
20.5, 28.6, 50.8, 60.9, 64.0, 116.1, 123.0, 128.3, 128.9,
129.1, 155.5; IR (film, nmax, cmꢂ1): 3303 (br), 2960 (w),
1606 (w), 1500 (w), 1257 (w), 1045 (w); Anal. Calcd for
C13H21NO2: C, 69.92; H, 9.48; N, 6.27; Found: C, 69.62;
H, 9.46; N, 6.27%.
4.4.4. N-(20-Hydroxy-30-methylphenyl)methyl-(S)-2-ami-
no-3-methylbutanol (1e). White crystalline solid (98 mg,
1
88%); mp 56–57 ꢀC; [a]D24 +17.3 (c 1.0, CHCl3); H NMR
4.4.8. N-(30-Chloro-20-hydroxyphenyl)methyl-(S)-2-
amino-3-methylbutanol (1i). White crystalline solid
(102 mg, 84%); mp 90–92 ꢀC, [a]D24 +13.5 (c 1.2, CHCl3);
1H NMR (CDCl3, 400 MHz): d 0.91 and 0.95 (6H,
2ꢁd, J¼6.8 Hz, 2ꢁCH3), 1.94 (1H, m, CH(CH3)2), 2.56
(1H, m, CHNH), 3.62 (1H, ABX, JAB¼11.6, JBX¼6.8 Hz,
CHaHbOH), 3.77 (1H, ABX, JAB¼11.2, JAX¼3.2 Hz,
CHaHbOH), 4.01 (2H, s, CH2NH), 6.50 (1H, apparent t, J¼
7.6 Hz, Ar), 6.90 (1H, d, J¼7.6 Hz, Ar), 7.19 (1H, d, J¼
8.0 Hz, Ar); 13C NMR (CDCl3, 100 MHz): d 18.4, 19.4, 28.2,
49.9, 60.3, 64.4, 119.6, 121.5, 123.1, 127.6, 129.6, 153.7; IR
(film, nmax, cmꢂ1): 3292 (br), 2965 (w), 1710 (w), 1589 (w),
1451 (m), 1288 (w); Anal. Calcd for C12H18ClNO2: C, 59.13;
H, 7.44; N, 5.75; Found: C, 59.14; H, 7.49; N, 5.62%.
(CDCl3, 400 MHz): d 1.01 and 1.04 (6H, 2ꢁd, J¼6.8 Hz,
2ꢁCH3), 1.98 (1H, m, CH(CH3)2), 2.29 (1H, s, CH3), 2.51
(1H, m, CHNH), 3.64 (1H, ABX, JAB¼11.2, JBX¼6.0 Hz,
CHaHbOH), 3.82 (1H, ABX, JAB¼11.2, JAX¼4.0 Hz,
CHaHbOH), 4.00 (2H, s, CH2NH), 5.24 (br s, NH and
OH), 6.74 (1H, apparent t, J¼7.2 Hz, Ar), 6.88 (1H, d, J¼
7.2 Hz, Ar), 7.03 (1H, d, J¼7.2 Hz, Ar); 13C NMR (CDCl3,
100 MHz): d 15.8, 18.8, 19.2, 28.6, 51.0, 61.0, 64.2, 118.8,
122.6, 125.3, 125.9, 130.0, 156.1; IR (film, nmax, cmꢂ1):
3416 (br), 2960 (w), 1597 (m), 1460 (m), 1262 (m), 1226
(m), 1079 (m), 1044 (m); Anal. Calcd for C13H21NO2: C,
69.92; H, 9.48; N, 6.27; Found: C, 69.93; H, 9.47; N, 6.20%.
4.4.5. N-(50-tert-Butyl-20-hydroxyphenyl)methyl-(S)-2-
amino-3-methylbutanol (1f). Colorless oil (115 mg,
87%); [a]2D4 +18.3 (c 1.5, CHCl3); 1H NMR (CDCl3,
400 MHz): d 1.01 and 1.03 (6H, 2ꢁd, J¼6.8 Hz, 2ꢁCH3),
1.31 (9H, s, 3ꢁCH3), 1.98 (1H, m, CH(CH3)2), 2.55
(1H, m, CHNH), 3.66 (1H, ABX, JAB¼11.2, JBX¼6.4 Hz,
CHaHbOH), 3.83 (1H, ABX, JAB¼11.2, JAX¼4.0 Hz,
CHaHbOH), 4.03 (2H, s, CH2NH), 5.24 (br s, NH and
OH), 6.81 (1H, d, J¼8.4 Hz, Ar), 7.04 (1H, s, Ar), 7.22 (1H,
d, J¼8.4 Hz, Ar); 13C NMR (CDCl3, 100 MHz): d 18.8,
19.2, 28.6, 31.6, 34.0, 51.2, 61.0, 64.2, 115.8, 122.3,
4.4.9. N-(20-Hydroxy-50-methoxyphenyl)methyl-(S)-2-
amino-3-methylbutanol (1j). Yellow viscous oil (110 mg,
92%); [a]2D4 +7.6 (c 1.2, CHCl3); 1H NMR (CDCl3,
400 MHz): d 0.96 and 1.00 (6H, 2ꢁd, J¼6.8 Hz, 2ꢁCH3),
1.94 (1H, m, CH(CH3)2), 2.49 (1H, m, CHNH), 3.61 (1H,
ABX, JAB¼11.2, JBX¼6.4 Hz, CHaHbOH), 3.74 (3H,
s, OCH3), 3.80 (1H, ABX, JAB¼11.2, JAX¼3.6 Hz,
CHaHbOH), 3.98 (2H, s, CH2NH), 4.98 (br s, NH and
OH), 6.59 (1H, s, Ar), 6.74 (2H, m, Ar); 13C NMR (CDCl3,
100 MHz): d 18.7, 19.2, 28.5, 50.8, 55.8, 60.8, 64.1, 113.6,

8732
V. Banphavichit et al. / Tetrahedron 63 (2007) 8727–8734
114.3, 116.7, 123.8, 151.6, 152.5; IR (film, nmax, cmꢂ1):
3304 (br), 2958 (w), 2361 (w), 1605 (w), 1498 (m), 1252
(m), 1151 (w), 1042 (w); Anal. Calcd for C13H21NO3: C,
65.25; H, 8.84; N, 5.85; Found: C, 64.96; H, 8.75; N, 5.85%.
3.54 (1H, ABX, JAB¼10.8, JBX¼4.8 Hz, CHaHbOH), 3.71
(1H, ABX, JAB¼11.2, JAX¼4.0 Hz, CHaHbOH), 3.98 (2H,
s, CH2NH), 6.74 (1H, d, J¼8.0 Hz, Ar), 6.84 (2H, m, Ar),
7.17 (2H, m, Ar), 7.24 (1H, m, Ar), 7.31 (2H, m, Ar); 13C
NMR (CDCl3, 100 MHz): d 37.3, 49.8, 59.5, 62.4, 116.9,
119.2, 121.1, 126.7, 128.6, 128.9, 129.1, 134.0, 137.8,
158.9; IR (film, nmax, cmꢂ1): 3322 (br), 2985 (w), 1595
(m), 1347 (w), 1259 (w), 1036 (m); Anal. Calcd for
C16H18ClNO2: C, 65.86; H, 6.22; N, 4.80; Found: C,
65.78; H, 6.15; N, 4.85%.
4.4.10. N-(30,50-Dimethyl-20-hydroxyphenyl)methyl-(S)-
2-amino-3-methylbutanol (1k). Colorless oil (98 mg,
83%); [a]2D4 +13.0 (c 1.2, CHCl3); 1H NMR (CDCl3,
400 MHz): d 0.93 (6H, apparent t, J¼7.2 Hz, 2ꢁCH3),
2.14 and 2.16 (6H, 2ꢁs, 2ꢁCH3), 2.58 (1H, m, CHNH),
3.60 (1H, ABX, JAB¼11.6, JBX¼6.8 Hz, CHaHbOH), 3.74
(1H, ABX, JAB¼11.6, JAX¼3.6 Hz, CHaHbOH), 3.91 (1H,
AB, J¼13.2 Hz, CHaHbNH), 4.00 (1H, AB, J¼13.2 Hz,
CHaHbNH), 6.67 (1H, s, Ar), 6.83 (1H, s, Ar); 13C NMR
(CDCl3, 100 MHz): d 15.9, 18.3, 19.3, 20.3, 27.9, 49.7,
60.1, 64.1, 120.5, 125.9, 127.5, 128.9, 131.6, 153.6; IR
(film, nmax, cmꢂ1): 3305 (br), 2959 (w), 1613 (w), 1480
(m), 1242 (m), 1153 (w), 1043 (w); Anal. Calcd for
C14H23NO2: C, 70.85; H, 9.77; N, 5.90; Found: C, 70.70;
H, 9.76; N, 5.82%.
4.4.14. N-(20-Hydroxy-40-methylphenyl)methyl-(S)-2-
amino-3-phenylpropanol (1v). White crystalline solid
(116 mg, 86%); mp 136.3–137.5 ꢀC; [a]D24 +28.7 (c 1.0,
CHCl3); 1H NMR (CDCl3, 400 MHz): d 2.24 (1H, s, CH3),
2.80 (1H, ABX, JAB¼13.6, JBX¼7.6 Hz, CHaHbPh), 2.88
(1H, ABX, JAB¼13.6, JAX¼6.4 Hz, CHaHbPh), 2.97
(1H, m, CHNH), 3.52 (1H, ABX, JAB¼11.2, JBX¼5.2 Hz,
CHaHbOH), 3.71 (1H, ABX, JAB¼11.2, JAX¼4.0 Hz,
CHaHbOH), 3.95 (2H, s, CH2NH), 5.07 (br s, NH and
OH), 6.75 (2H, m, Ar), 6.96 (1H, d, J¼8.0 Hz, Ar), 7.18
(2H, m, Ar), 7.24 (1H, m, Ar), 7.31 (2H, m, Ar); 13C
NMR (CDCl3, 100 MHz): d 20.7, 37.5, 50.2, 59.6, 62.4,
116.5, 122.2, 126.4, 128.3, 128.6, 129.1, 129.5, 138.2,
155.6; IR (film, nmax, cmꢂ1): 3322 (br), 2921 (w), 1617
(w), 1587 (w), 1454 (m), 1348 (w), 1284 (w), 1109 (m),
1046 (m); Anal. Calcd for C17H21NO2: C, 75.25; H, 7.80;
N, 5.16; Found: C, 75.23; H, 7.78; N, 5.25%.
4.4.11. N-(30,50-Di-tert-butyl-20-hydroxyphenyl)methyl-
(S)-2-amino-3-methylbutanol (1l). White crystalline solid
(140 mg, 87%); mp 55–57 ꢀC; [a]D24 +17.3 (c 2.0, CHCl3);
1H NMR (CDCl3, 400 MHz): d 1.06 and 1.09 (6H, 2ꢁd,
J¼7.2 Hz, 2ꢁCH3), 1.38 (9H, s, C(CH3)3), 1.52 (9H, s,
C(CH3)3), 2.03 (1H, m, CH(CH3)2), 2.56 (1H, m, CHNH),
3.72 (1H, ABX, JAB¼11.2, JBX¼5.6 Hz, CHaHbOH), 3.88
(1H, ABX, JAB¼11.2, JAX¼3.6 Hz, CHaHbOH), 4.05 (1H,
AB, J¼13.6 Hz, CHaHbNH), 4.12 (1H, AB, J¼13.6 Hz,
CHaHbNH), 6.98 (1H, s, Ar), 7.33 (1H, s, Ar); 13C NMR
(CDCl3, 100 MHz): d 19.1, 19.2, 28.7, 29.7, 31.8, 34.2,
35.0, 51.8, 61.3, 64.0, 122.7, 123.1, 123.2, 136.1, 140.7,
154.5; IR (film, nmax, cmꢂ1): 3316 (br), 2958 (m), 1605
(w), 1475 (m), 1237 (m), 1165 (w), 1083 (w); Anal. Calcd
for C20H35NO2: C, 74.72; H, 10.97; N, 4.36; Found: C,
74.90; H, 10.97; N, 4.48%.
4.4.15. N-(30,50-Di-tert-butyl-20-hydroxyphenyl)methyl-
(S)-2-amino-3,3-dimethylbutanol (1x). White crystalline
solid (143 mg, 85%); mp 57–59 ꢀC; [a]D24 +16.7 (c 2.0,
CHCl3); 1H NMR (CDCl3, 400 MHz): d 1.06 (9H, s,
C(CH3)3), 1.34 (9H, s, C(CH3)3), 1.49 (9H, s, C(CH3)3),
2.40 (1H, ABX, JAX¼3.6, JBX¼5.2 Hz, CHC(CH3)3), 3.77
(1H, ABX, JAB¼11.2, JBX¼5.2 Hz, CHaHbOH), 4.02 (1H,
ABX, JAB¼12.0, JAX¼3.6 Hz, CHaHbOH), 4.19 (2H, d,
J¼13.2 Hz, CH2NH), 6.95 (1H, s, Ar), 7.29 (1H, s, Ar);
13C NMR (CDCl3, 100 MHz): d 27.6, 29.7, 31.7, 34.2,
34.3, 35.0, 53.6, 61.6, 67.5, 122.9, 123.1, 123.3, 136.1,
140.6, 154.6; IR (film, nmax, cmꢂ1): 2957 (w), 1478 (w),
1363 (w), 1237 (w), 1114 (w); Anal. Calcd for
C21H37NO2: C, 75.17; H, 11.12; N, 4.17; Found: C, 75.18;
H, 11.04; N, 4.15%.
4.4.12. N-(20-Hydroxy-40-phenylphenyl)methyl-(S)-2-
amino-3-phenylpropanol (1t). White crystalline solid
(145 mg, 87%); mp 134.8–136.3 ꢀC; [a]D24 +26.8 (c 1.0,
1
CHCl3); H NMR (CDCl3, 400 MHz): d 2.83 (1H, ABX,
JAB¼13.6, JBX¼7.2 Hz, CHaHbPh), 2.92 (1H, ABX,
JAB¼13.6, JAX¼6.4 Hz, CHaHbPh), 3.01 (1H, m, CHNH),
3.55 (1H, ABX, JAB¼11.2, JBX¼5.2 Hz, CHaHbOH), 3.75
(1H, ABX, JAB¼11.2, JAX¼4.0 Hz, CHaHbOH), 4.04 (2H,
s, CH2NH), 5.16 (br s, NH and OH), 7.03 (2H, m, Ar),
7.12 (1H, s, Ar), 7.20 (2H, m, Ar), 7.26 (1H, m, Ar), 7.34
(3H, m, Ar), 7.43 (2H, m, Ar), 7.59 (2H, m, Ar); 13C
NMR (CDCl3, 100 MHz): d 37.2, 49.8, 59.3, 62.4, 115.1,
118.0, 121.8, 126.7 (overlapping signals), 126.9, 127.3,
4.4.16. N-(20-Hydroxy-50-methylphenyl)methyl-(S)-2-
amino-3,3-dimethylbutanol (1y). White crystalline solid
(100 mg, 84%); mp 62–64 ꢀC; [a]D24 +7.6 (c 1.0, CHCl3);
1H NMR (CDCl3, 400 MHz): d 1.03 (9H, s, 3ꢁCH3), 2.27
(1H, s, CH3), 2.41 (1H, ABX, JAX¼3.6, JBX¼5.6 Hz,
CHC(CH3)3), 3.72 (1H, ABX, JAB¼11.2, JBX¼6.0 Hz,
CHaHbOH), 3.98 (1H, ABX, JAB¼11.2, JAX¼3.6 Hz, CHa-
HbOH), 4.14 (2H, d, J¼13.6 Hz, CH2NH), 4.76 (br s, NH
and OH), 6.79 (1H, d, J¼8.0 Hz, Ar), 6.85 (1H, s, Ar),
7.01 (1H, d, J¼8.0 Hz, Ar); 13C NMR (CDCl3, 100 MHz):
d 20.5, 27.5, 34.2, 53.0, 61.4, 67.7, 116.1, 123.0, 128.2,
129.0, 129.2, 155.6; IR (film, nmax, cmꢂ1): 3420 (br), 2958
(m), 1597 (m), 1469 (m), 1263 (m), 1226 (m), 1085 (m),
1042 (m); Anal. Calcd for C14H23NO2: C, 70.85; H, 9.77;
N, 5.90; Found: C, 70.89; H, 9.80; N, 5.98%.
128.7, 129.2, 138.0, 140.8, 142.0, 158.2; IR (film, nmax
,
cmꢂ1): 3315 (br), 3028 (br), 2925 (w), 1602 (w), 1567
(m), 1486 (m), 1458 (m), 1306 (w), 1205 (w), 1039 (m);
Anal. Calcd for C21H22NO2: C, 79.25; H, 6.95; N, 4.20;
Found: C, 78.94; H, 6.92; N, 4.21%.
4.4.13. N-(40-Chloro-20-hydroxyphenyl)methyl-(S)-2-
amino-3-phenylpropanol (1u). White crystalline solid
(121 mg, 83%); mp 143.6–144.5 ꢀC; [a]D24 +35.4 (c 1.0,
1
CHCl3); H NMR (CDCl3, 400 MHz): d 2.80 (1H, ABX,
JAB¼13.6, JBX¼7.6 Hz, CHaHbPh), 2.88 (1H, ABX,
4.4.17. N-(20-Hydroxy-30-methylphenyl)methyl-(S)-2-
amino-3,3-dimethylbutanol (1z). White crystalline solid
JAB¼13.6, JAX¼6.4 Hz, CHaHbPh), 2.97 (1H, m, CHNH),

V. Banphavichit et al. / Tetrahedron 63 (2007) 8727–8734
8733
(106 mg, 89%); mp 60–62 ꢀC; [a]D24 +6.4 (c 1.0, CHCl3); 1H
NMR (CDCl3, 400 MHz): d 1.05 (9H, s, 3ꢁCH3), 2.31 (1H, s,
CH3), 2.38 (1H, ABX, JAX¼3.6, JBX¼6.0 Hz, CHC(CH3)3),
3.68 (1H, ABX, JAB¼11.2, JBX¼6.0 Hz, CHaHbOH),
3.97 (1H, ABX, JAB¼11.2, JAX¼3.6 Hz, CHaHbOH), 4.03
(1H, AB, J¼13.6 Hz, CHaHbNH), 4.15 (1H, AB,
J¼13.6 Hz, CHaHbNH), 5.21 (br s, NH and OH), 6.76
(1H, apparent t, J¼7.6 Hz, Ar), 6.89 (1H, d, J¼7.2 Hz,
Ar), 7.10 (1H, d, J¼7.2 Hz, Ar); 13C NMR (CDCl3,
100 MHz): d 15.9, 27.5, 34.2, 53.3, 61.5, 67.9, 118.8,
122.9, 125.3, 126.0, 130.0, 156.2; IR (film, nmax, cmꢂ1):
3427 (br), 2958 (w), 1597 (w), 1470 (m), 1263 (w), 1227
(w), 1084 (w), 1042 (w); Anal. Calcd for C14H23NO2:
C, 70.85; H, 9.77; N, 5.90; Found: C, 70.72; H, 9.90;
N, 5.85%.
(1H, ABX, JAB¼13.6, JBX¼9.2 Hz, CHaHbPh), 2.98 (1H,
ABX, JAB¼13.6, JAX¼4.8 Hz, CHaHbPh), 3.19 (1H, m,
CHNH), 3.71 (2H, m, CH2OH), 3.88 (1H, AB, J¼13.6 Hz,
CHaHbN), 4.01 (1H, AB, J¼13.6 Hz, CHaHbNH), 6.83
(2H, m, Ar), 7.01 (1H, d, J¼8.0 Hz, Ar), 7.20 (2H, m, Ar),
7.27 (2H, m, Ar), 7.34 (2H, m, Ar); 13C NMR (CDCl3,
100 MHz): d 31.7, 35.7, 57.9, 60.9, 66.2, 116.2, 119.2,
121.9, 126.5, 128.7, 128.8, 128.9, 129.0, 129.1, 138.9,
157.7; IR (film, nmax, cmꢂ1): 3397 (br), 2935 (w), 1591
(m), 1488 (m), 1257 (m), 1031 (w); Anal. Calcd for
C17H21NO2: C, 75.25; H, 7.80; N, 5.16. Found: C, 75.29;
H, 7.90; N, 4.88%.
4.6.3. N-(30,50-Di-tert-butyl-20-hydroxyphenyl)methyl-N-
methyl-(S)-2-amino-3,3-dimethylbutanol (5c). Colorless
oil (63 mg, 60%); [a]2D4 +8.3 (c 1.0, CHCl3); 1H NMR
(CDCl3, 400 MHz): d 1.08 (9H, s, C(CH3)3), 1.32 (9H, s,
C(CH3)3), 1.47 (9H, s, C(CH3)3), 2.49 (3H, s, NCH3), 2.71
(1H, ABX, JAX¼3.6, JBX¼11.6 Hz, CHC(CH3)3), 4.02
(1H, ABX, JAB¼11.6, JBX¼3.6 Hz, CHaHbOH), 4.10 (1H,
ABX, JAB¼11.6, JAX¼6.4 Hz, CHaHbOH), 4.14 (1H, AB,
J¼13.2 Hz, CHaHbN), 4.21 (1H, AB, J¼13.6 Hz, CHaHbN),
6.91 (1H, s, Ar), 7.25 (1H, s, Ar); 13C NMR (CDCl3,
100 MHz): d 28.6, 29.6, 31.7, 34.2, 34.9, 35.2, 38.2, 60.2,
62.0, 73.3, 121.6, 122.7, 123.8, 135.3, 140.4, 154.3; Anal.
Calcd for C22H39NO2: C, 75.59; H, 11.25; N, 4.01; Found:
C, 75.13; H, 11.28; N, 4.01%.
4.5. General procedure for the synthesis of chiral
N-salicyl-b-aminoalcohol ligands 5
The oxazolidine was prepared starting from the multicompo-
nent reaction between a phenol, paraformaldehyde, and an
aminoalcohol as described in the general procedure for the
synthesis of 1.
Sodium borohydride (2.5 mmol) was dissolved in anhydrous
THF (10 mL) at 0 ꢀC with vigorous stirring. Then trifluoro-
acetic acid (2.5 mmol) was added dropwise to a suspension
of metal hydride. A solution of the partially purified oxazol-
idine in anhydrous THF (3 mL) was added dropwise to
a cooled mixture. After the addition, the reaction mixture
was stirred for 1 h at room temperature. The suspension
was cooled and decomposed off cautiously by 10% sodium
hydroxide aqueous solution. The mixture was concentrated
and extracted with ethyl acetate (3ꢁ10 mL). The organic
layer was dried over anhydrous Na2SO4 and evaporated in
vacuo. The oily residue was purified by flash column chro-
matography using hexanes and ethyl acetate as eluant to
obtain chiral N-methyl-N-salicyl-b-aminoalcohols 5.
4.6.4. N-(20-Hydroxy-50-phenylphenyl)methyl-N-methyl-
(R)-2-amino-2-phenylethanol (5d). White crystalline solid
(70 mg, 60%); mp 136–138 ꢀC; [a]D24 ꢂ96.8 (c 1.2, CHCl3);
1H NMR (CDCl3, 400 MHz): d 2.33 (3H, s, NCH3),
3.76 (1H, AB, J¼13.6 Hz, CHaHbNH), 3.91 (1H, AB,
J¼13.6 Hz, CHaHbNH), 3.96 (1H, ABX, JAX¼5.6, JBX
¼
8.0 Hz, PhCHN), 4.02 (1H, ABX, JAB¼11.2, JBX¼5.4 Hz,
CHaHbOH), 4.23 (1H, ABX, JAB¼11.6, JAX¼8.4 Hz,
CHaHbOH), 6.97 (1H, d, J¼8.4 Hz, Ar), 7.22 (1H, s, Ar),
7.33 (3H, m, Ar), 7.44 (5H, m, Ar), 7.55 (2H, m, Ar); 13C
NMR (CDCl3, 100 MHz): d 37.4, 58.0, 62.1, 69.2, 115.9,
116.6, 122.0, 126.5, 126.6, 127.4, 127.5, 128.5, 128.7,
129.1, 132.4, 134.9, 140.9, 157.4; HRMS (FAB+) calcd for
C22H24NO2 (M$H+): 334.1807, found: 334.1808.
4.6. Physical properties and spectroscopic and analytical
spectra of new ligands
4.6.1. N-(50-tert-Butyl-20-hydroxyphenyl)methyl-N-meth-
yl-(1R,2S)-1-aminoindan-2-ol (5a). White crystalline solid
(57 mg, 52%); mp 82–84 ꢀC; [a]D24 +18.3 (c 1.0, CHCl3); 1H
NMR (CDCl3, 400 MHz): d 1.35 (9H, s, C(CH3)3), 2.37
(3H, s, NCH3), 3.03 (1H, ABX, JAB¼17.6, JBX¼4.8 Hz,
ArCHaHbCHOH), 3.28 (1H, ABX, JAB¼17.6, JAX¼8.8 Hz,
ArCHaHbCHOH), 4.17 (2H, AB, J¼13.8 Hz, CH2NH),
4.46 (1H, d, J¼7.6 Hz, NCHCHOH), 4.93 (1H, m,
NCHCHOH), 6.95 (1H, d, J¼8.8 Hz, Ar), 7.08 (1H, s, Ar),
7.34 (3H, m, Ar), 7.45 (2H, m, Ar); 13C NMR (100 MHz,
CDCl3): d 31.6, 34.0, 38.1, 40.5, 58.8, 68.5, 73.1, 115.9,
120.3, 125.6, 125.8, 125.9, 126.5, 127.2, 129.0, 137.4,
141.2, 142.2, 155.2; IR (film, nmax, cmꢂ1): 3316 (br), 2921
(w), 1591 (w), 1472 (w), 1256 (w), 1089 (w); HRMS
(FAB+) calcd for C21H28NO2 (M$H+): 326.2120, found:
326.2120.
4.6.5. N-(20-Hydroxy-50-methylphenyl)methyl-N-methyl-
(S)-2-amino-3-methylbutanol (5e). Colorless oil (51 mg,
57%); [a]2D4 +12.6 (c 1.0, CHCl3); 1H NMR (CDCl3,
400 MHz): d 1.03 and 1.11 (6H, 2ꢁd, J¼6.8 Hz, 2ꢁCH3),
2.06 (1H, m, CH(CH3)2), 2.32 (3H, s, CH3Ar), 2.39 (3H, s,
NCH3), 2.58 (1H, m, CHN), 3.88 (1H, ABX, JAB¼12.0,
JBX¼7.2 Hz, CHaHbOH), 3.95 (1H, ABX, JAB¼11.6, JAX
¼
3.2 Hz, CHaHbOH), 4.02 (2H, s, CH2NH), 6.64 (1H, d,
J¼7.2 Hz, Ar), 6.71 (1H, s, Ar), 6.91 (1H, d, J¼7.6 Hz,
Ar); 13C NMR (CDCl3, 100 MHz): d 20.1, 21.2, 21.4,
26.7, 35.9, 59.2, 70.3, 116.6, 118.6, 119.9, 128.6, 138.9,
157.2; HRMS (FAB+) calcd for C14H24NO2 (M$H+):
238.1807, found: 238.1808.
4.6.6. N-(20-Hydroxy-40-phenylphenyl)methyl-N-methyl-
(S)-2-amino-3-methylbutanol (5f). White crystalline solid
(60 mg, 58%); mp 126–128 ꢀC; [a]D24 ꢂ11.2 (c 1.0,
CHCl3); 1H NMR (CDCl3, 400 MHz): d 1.05 and 1.13
(6H, 2ꢁd, J¼6.8 Hz, 2ꢁCH3), 2.06 (1H, m, CH(CH3)2),
2.45 (3H, s, NCH3), 2.66 (1H, m, CHN), 3.91 (1H, ABX,
4.6.2. N-(20-Hydroxyphenyl)methyl-N-methyl-(S)-2-
amino-3-phenylpropanol (5b). White crystalline solid
(84 mg, 62%); mp 63–65 ꢀC; [a]D24 ꢂ35.5 (c 1.8, CHCl3);
1H NMR (CDCl3, 400 MHz): d 2.41 (3H, s, NCH3), 2.60

8734
V. Banphavichit et al. / Tetrahedron 63 (2007) 8727–8734
Mansawat, W.; Bhanthumnavin, W.; Vilaivan, T. Tetrahedron
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6. Li, Y.; He, B.; Qin, B.; Feng, X.; Zhang, G. J. Org. Chem. 2004,
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7. (a) Narasimhan, S.; Velmathi, S.; Balakumar, R.;
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Tetrahedron: Asymmetry 2003, 14, 113–117.
JAB¼11.6, JBX¼7.2 Hz, CHaHbOH), 3.98 (1H, ABX, JAB
¼
11.6, JAX¼3.2 Hz, CHaHbOH), 4.11 (2H, s, CH2NH),
7.06–7.15 (3H, m, Ar), 7.28 (1H, s, Ar), 7.36 (1H, m, Ar),
7.45 (1H, apparent t, J¼7.2 Hz, Ar), 7.61 (2H, m, Ar); 13C
NMR (CDCl3, 100 MHz): d 20.2, 21.2, 21.5, 26.8, 36.0,
59.3, 70.5, 114.7, 118.0, 120.6, 127.0, 127.3, 128.7, 129.3,
140.8, 142.2, 158.0; HRMS (FAB+) calcd for C19H26NO2
(M$H+): 300.1964, found: 300.1967.
8. (a) Suwa, T.; Sugiyama, E.; Shibata, I.; Baba, A. Synthesis
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Acknowledgements
This work was supported by the Thailand Toray Science
Foundation (T.V.) and the Thailand Research Fund under
the Royal Golden Jubilee Ph.D. Project (V.B.). We thank
Ms. Wanna Bannarukkul and Mr. Nitirat Chimnoi for their
technical assistance.
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